Relaxed complex scheme suggests novel inhibitors for the lyase activity of DNA polymerase beta

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Research

Background:

• DNA polymerase beta (pol β) is crucial in base excision repair and contributes to resistance against various cancer chemotherapies.
• Overexpression and mutations in pol β reduce anticancer drug efficacy and increase genomic instability, highlighting its role in cancer progression.
• Existing pol β inhibitors lack potency and specificity, necessitating the discovery of novel therapeutic agents.

Purpose of the Study:

• To identify novel, potent, and specific inhibitors of DNA polymerase beta (pol β) using advanced computational screening.
• To explore the potential of pol β as a therapeutic target for overcoming chemotherapeutic resistance in cancer.

Main Methods:

• Employed relaxed complex scheme virtual screening (RCSVS) to account for full receptor flexibility.
• Screened large compound libraries (NCI diversity set, DrugBank, fragmental library) against an ensemble of 11 dominant pol β receptor structures.
• Evaluated binding affinity of identified compounds to the lyase active site of pol β.

Main Results:

• Identified novel compounds with predicted higher binding affinity to the pol β lyase active site compared to the known inhibitor pamoic acid (PA).
• The virtual screening approach successfully filtered diverse compound libraries for potential pol β inhibitors.
• The study identified promising candidates for further development as anticancer therapeutics.

Conclusions:

• DNA polymerase beta (pol β) is a viable therapeutic target for enhancing cancer treatment efficacy.
• RCSVS is an effective method for discovering novel inhibitors with potential therapeutic applications.
• The identified compounds warrant further investigation for their preclinical and clinical utility in cancer therapy.